EP1805307A1 - Protection of biologically active molecules using amphiphiles - Google Patents
Protection of biologically active molecules using amphiphilesInfo
- Publication number
- EP1805307A1 EP1805307A1 EP05795379A EP05795379A EP1805307A1 EP 1805307 A1 EP1805307 A1 EP 1805307A1 EP 05795379 A EP05795379 A EP 05795379A EP 05795379 A EP05795379 A EP 05795379A EP 1805307 A1 EP1805307 A1 EP 1805307A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- biologically active
- active compound
- saint
- molecule
- sirna
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000009881 electrostatic interaction Effects 0.000 claims abstract 4
- 150000001875 compounds Chemical class 0.000 claims description 45
- 230000000694 effects Effects 0.000 claims description 21
- 102000004190 Enzymes Human genes 0.000 claims description 18
- 108090000790 Enzymes Proteins 0.000 claims description 18
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 4
- 239000003446 ligand Substances 0.000 abstract 1
- 108020004459 Small interfering RNA Proteins 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
- 108090000623 proteins and genes Proteins 0.000 description 6
- 238000001890 transfection Methods 0.000 description 6
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108091034117 Oligonucleotide Proteins 0.000 description 3
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
- C12N15/88—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation using microencapsulation, e.g. using amphiphile liposome vesicle
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/111—General methods applicable to biologically active non-coding nucleic acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/14—Type of nucleic acid interfering N.A.
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2320/00—Applications; Uses
- C12N2320/50—Methods for regulating/modulating their activity
- C12N2320/51—Methods for regulating/modulating their activity modulating the chemical stability, e.g. nuclease-resistance
Definitions
- the present invention relates to a process to protect a biologically active compound against the effects of for instance enzymes, chemicals, oxygen, radicals or sunlight. Further the invention relates to a vehicle to protect a biological active compound against the effects of for instance enzymes, chemicals, oxygen, radicals or sunlight. The invention also relates to the application of a SAINT-molecule to protect a biological active compound against the effects of for instance enzymes, chemicals, oxygen, radicals or sunlight.
- biologically active compounds such as siRNA, RNA, DNA, proteins and peptides are sensitive for the effects (e.g. degradation) of for instance enzymes, chemicals, oxygen, radicals or sunlight.
- biologically active compounds such as siRNA, RNA, DNA, oligonucleotides or derivates thereof
- proteins and peptides can only be transported as dry matter, or as a stabilized, glycerol or DMSO containing solution.
- the solutions to be transported or dry matters are kept on dry ice, or are cooled in another way. Consequently, the transportation of these compounds is very expensive.
- Another disadvantage of transporting biologically active compounds as dry matter is the fact that during the dissolution of the biologically active compound a conformational change may occur. As a result, not all biologically active matter will regain its original function.
- glycerol (or DMSO) has shown to have a negative effect on the activity of the biologically active compound when the biologically active compound is diluted before application.
- the solution found in the state of the art to circumvent these disadvantages is to replace the glycerol (or DMSO) by threhalose.
- Threhalose is a sugar. Although in theory no conformational change occurs when dissolving the biologically active compound in threhalose, there are some other disadvantages when using threhalose. A particular disadvantage is that threhalose has an adverse effect on the desired enzymatic activity of the proteins.
- threhalose is not used to package DNA, RNA, siRNA en oligonucleotides or derivatives thereof. After complexation with threhalose (and other sugars) DNA,RNA etc, are laboriously to be dissolved, as they can also be characterized as sugars.
- the present invention aims at solving the disadvantages mentioned above.
- the invention aims to provide for a process to protect a biologically active compound against the effects of for instance enzymes, chemicals, oxygen, radicals or sunlight.
- the invention also aims to provide for a vehicle to protect a biologically active compound against the effects of enzymes, chemicals, oxygen, radicals or sunlight whereby the disadvantages mentioned above can be circumvented.
- transport is understood to mean both the packaging of the biologically active compound in a transportation container, and the subsequent conveyance of this container by means of transportation means, such as carriers, etc., as well as the transport of individual biologically active molecules, which are each separately enwrapped by the protecting compounds.
- the present invention provides for a process as mentioned in the preamble, which process is characterised by the measures according to claim 1.
- the biologically active compound has become completely protected from effects of enzymes, chemicals, oxygen, radicals or sunlight. Furthermore, completely no or no functional inhibitory conformational changes of the biological compound occur.
- the invention provides for a vehicle as mentioned in the pre-amble, characterized by the measures as described in claim 4.
- the vehicle of the present invention provides a very reliable and simple solution for transporting a biologically active compound in such a way that the biologically active compound will not become damaged, for instance by the effect of enzymes, chemicals, oxygen, radicals or sunlight, or a conformational change occurs.
- a SAINT-molecule protects a biologically active compound against the effect of for instance enzymes, chemicals, oxygen, radicals or sunlight, which is characterized in that the biologically active compound is contacted with the biologically active compound, causing the biologically active compounds to interact with the SAINT-molecule.
- the biologically active compound which can be chosen from, for instance, siRNA, RNA, DNA, oligonucleotides or derivatives thereof, proteins and peptides, is actually enwrapped by one ore more SAINT-molecules.
- the saint molecules may all be of the same kind, but it is also possible that a mixture of different SAINT-molecules is applied, which can be connected to the biological active compound. This interaction is a hydrogen-bond.
- the vehicle of the present invention consisting of the biologically active compound and the SAINT-molecule or SAINT-molecules enwrapping it, can be kept without occurring a separation of the biologically active compound and the SAINT-molecules.
- the biologically active compound when the biologically active compound has to fulfil its function, it is not suffering any functional hindrance from the SAINT-molecules present. Therefore the biologically active compounds can freely operate and can easily be applied in basically any biological assay.
- a remarkably great advantage of the present invention is that no separation of the SAINT-molecule (s) from the biological active compound is needed, because the saint-molecule (s) have no inhibitory effect in the buffer. The molecule will be diluted to such a great extent, that no inhibitory effect will be shown. Furthermore it is biologically degradable, without forming any toxic compounds.
- siRNA when directed to a specific gene, is able to silence the gene-expression by inhibition of the mRNA translation.
- SiRNA needs to be stored as dried powder and, after dissolution, aliquots are stored at -2O 0 C. Regardless of aliquots being prepared, the reproducibility of (the results obtained over time using) such aliquots is weak.
- the delivery of siRNA to cells has been described in patents EP-0755924 and US 5,853,694.
- siRNA 25 micrograms of siRNA were complexed with 0,5 ml of SAINT-MIX. Per transfection 20 ⁇ l of this (preservation) -complex is used. Transfection was performed as described in detail in EP-0755924.
- the efficacy of the siRNA-transfection is validated by measuring the enzyme activity of the silenced gene according to a standard enzyme assay. Lifetime of the enzyme is approximately 5 days. Therefore, after one single transfection with 1 Dg siRNA, about 50% enzyme activity can be measured after 48 hours and almost no enzyme activity can be measured after 10 days, as shown in the figure 1 below.
- siRNA complexed with SAINT-RED is active over a 9 month- period while the aliguoted siRNA has lost almost all its activity within 2 days.
- results show that the siRNA/SAINT prevention complex is even more active, up to 5 months, when compared with the freshly prepared siRNA/SAINT complex. This indicates the strong protective character of SAINT-molecules towards biologically active compounds.
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biomedical Technology (AREA)
- Organic Chemistry (AREA)
- Wood Science & Technology (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Zoology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Plant Pathology (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Physics & Mathematics (AREA)
- Medicinal Preparation (AREA)
- Enzymes And Modification Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Saccharide Compounds (AREA)
- Peptides Or Proteins (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Immobilizing And Processing Of Enzymes And Microorganisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Apparatus Associated With Microorganisms And Enzymes (AREA)
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SI200530618T SI1805307T1 (en) | 2004-10-21 | 2005-10-20 | Protection of biologically active molecules using amphiphiles |
PL05795379T PL1805307T3 (en) | 2004-10-21 | 2005-10-20 | Protection of biologically active molecules using amphiphiles |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NL1027311A NL1027311C2 (en) | 2004-10-21 | 2004-10-21 | New vehicle, useful for the transport to the nucleus of a DNA-modifying enzyme/molecule which is combined with a SAINT-molecule or a combination of several entities |
NL1027417A NL1027417C2 (en) | 2004-10-21 | 2004-11-04 | New vehicle, useful for the transport to the nucleus of a DNA-modifying enzyme/molecule which is combined with a SAINT-molecule or a combination of several entities |
NL1027479A NL1027479C2 (en) | 2004-10-21 | 2004-11-10 | Protection of biologically active molecules with the help of amphiphiles. |
PCT/NL2005/000752 WO2006043809A1 (en) | 2004-10-21 | 2005-10-20 | Protection of biologically active molecules using amphiphiles |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1805307A1 true EP1805307A1 (en) | 2007-07-11 |
EP1805307B1 EP1805307B1 (en) | 2009-01-14 |
Family
ID=35583431
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP05795367A Not-in-force EP1805305B1 (en) | 2004-10-21 | 2005-10-20 | Vehicle for the transport of a chosen molecule to a cell |
EP05795379A Active EP1805307B1 (en) | 2004-10-21 | 2005-10-20 | Protection of biologically active molecules using amphiphiles |
EP05795375A Not-in-force EP1805306B1 (en) | 2004-10-21 | 2005-10-20 | Vehicle to transport a dna-modifying enzyme to a genome |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP05795367A Not-in-force EP1805305B1 (en) | 2004-10-21 | 2005-10-20 | Vehicle for the transport of a chosen molecule to a cell |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP05795375A Not-in-force EP1805306B1 (en) | 2004-10-21 | 2005-10-20 | Vehicle to transport a dna-modifying enzyme to a genome |
Country Status (16)
Country | Link |
---|---|
US (4) | US20070225230A1 (en) |
EP (3) | EP1805305B1 (en) |
JP (2) | JP2008517904A (en) |
KR (1) | KR20070073796A (en) |
AT (3) | ATE420173T1 (en) |
AU (1) | AU2005296360B2 (en) |
CA (2) | CA2583860A1 (en) |
DE (3) | DE602005012420D1 (en) |
DK (3) | DK1805307T3 (en) |
ES (3) | ES2318549T3 (en) |
NL (1) | NL1027479C2 (en) |
NO (3) | NO20071600L (en) |
PL (3) | PL1805307T3 (en) |
PT (3) | PT1805306E (en) |
SI (3) | SI1805307T1 (en) |
WO (3) | WO2006043811A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101848703B (en) * | 2007-09-07 | 2014-04-16 | 辛沃鲁克斯Ip有限公司 | Improved liposomes and uses thereof |
DE102008032594A1 (en) | 2008-07-11 | 2010-01-14 | Qiagen Gmbh | transfection |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5077211A (en) * | 1988-07-06 | 1991-12-31 | Applied Genetics, Inc. | Purification and administration of dna repair enzymes |
US5641625A (en) * | 1992-05-22 | 1997-06-24 | Isis Pharmaceuticals, Inc. | Cleaving double-stranded DNA with peptide nucleic acids |
KR100252547B1 (en) * | 1991-09-05 | 2000-09-01 | 프레드 마리얀스키 | Targeted delivery of poly- or oligonucleotides to cells |
US6083741A (en) * | 1994-11-17 | 2000-07-04 | Imperial College Of Science Technology And Medicine | Internalisation of DNA, using conjugates of poly-l-lysine and an integrin receptor ligand |
NL1000884C2 (en) * | 1995-07-25 | 1997-01-28 | Univ Groningen | Transport vehicles for macromolecules. |
US6726894B1 (en) * | 1995-07-25 | 2004-04-27 | Synvolux Ip B.V. | Transport vehicles for macromolecules |
US5958894A (en) * | 1997-04-04 | 1999-09-28 | Megabios Corporation | Amphiphilic biguanide derivatives |
EP1401818A2 (en) * | 2001-05-30 | 2004-03-31 | Targesome, Inc. | Targeted multivalent macromolecules |
GB0117964D0 (en) * | 2001-07-24 | 2001-09-19 | Imp College Innovations Ltd | Control of gene expression |
CA2455598A1 (en) * | 2001-07-27 | 2003-02-13 | Targesome, Inc. | Lipid constructs as therapeutic and imaging agents |
GB0124391D0 (en) * | 2001-10-11 | 2001-11-28 | Gene Expression Technologies L | Control of gene expression |
CA2487274A1 (en) * | 2002-05-06 | 2003-11-13 | Nucleonics Inc. | Spermine chemically linked to lipids and cell-specific targeting molecules as a transfection agent |
US20060247192A1 (en) * | 2002-12-05 | 2006-11-02 | Jenkinson John D | Control of apoptosis |
AU2003225410A1 (en) * | 2003-03-21 | 2004-10-11 | Academisch Ziekenhuis Leiden | Modulation of exon recognition in pre-mrna by interfering with the secondary rna structure |
ITMI20030821A1 (en) * | 2003-04-18 | 2004-10-19 | Internat Ct For Genetic En Gineering And | CHEMICAL POLYPEPTIDES AND THEIR USE. |
-
2004
- 2004-11-10 NL NL1027479A patent/NL1027479C2/en active Search and Examination
-
2005
- 2005-10-20 CA CA002583860A patent/CA2583860A1/en not_active Abandoned
- 2005-10-20 ES ES05795375T patent/ES2318549T3/en active Active
- 2005-10-20 PT PT05795375T patent/PT1805306E/en unknown
- 2005-10-20 EP EP05795367A patent/EP1805305B1/en not_active Not-in-force
- 2005-10-20 AU AU2005296360A patent/AU2005296360B2/en not_active Ceased
- 2005-10-20 EP EP05795379A patent/EP1805307B1/en active Active
- 2005-10-20 PL PL05795379T patent/PL1805307T3/en unknown
- 2005-10-20 DE DE602005012420T patent/DE602005012420D1/en active Active
- 2005-10-20 PT PT05795367T patent/PT1805305E/en unknown
- 2005-10-20 KR KR1020077008948A patent/KR20070073796A/en not_active Application Discontinuation
- 2005-10-20 AT AT05795375T patent/ATE420173T1/en not_active IP Right Cessation
- 2005-10-20 CA CA2584633A patent/CA2584633C/en not_active Expired - Fee Related
- 2005-10-20 DE DE602005012303T patent/DE602005012303D1/en active Active
- 2005-10-20 WO PCT/NL2005/000754 patent/WO2006043811A1/en active Application Filing
- 2005-10-20 DK DK05795379T patent/DK1805307T3/en active
- 2005-10-20 WO PCT/NL2005/000753 patent/WO2006043810A1/en active Application Filing
- 2005-10-20 SI SI200530618T patent/SI1805307T1/en unknown
- 2005-10-20 AT AT05795367T patent/ATE420172T1/en not_active IP Right Cessation
- 2005-10-20 PL PL05795375T patent/PL1805306T3/en unknown
- 2005-10-20 PL PL05795367T patent/PL1805305T3/en unknown
- 2005-10-20 DK DK05795367T patent/DK1805305T3/en active
- 2005-10-20 AT AT05795379T patent/ATE420954T1/en not_active IP Right Cessation
- 2005-10-20 EP EP05795375A patent/EP1805306B1/en not_active Not-in-force
- 2005-10-20 DE DE602005012304T patent/DE602005012304D1/en active Active
- 2005-10-20 SI SI200530616T patent/SI1805305T1/en unknown
- 2005-10-20 JP JP2007537824A patent/JP2008517904A/en active Pending
- 2005-10-20 SI SI200530617T patent/SI1805306T1/en unknown
- 2005-10-20 ES ES05795379T patent/ES2318550T3/en active Active
- 2005-10-20 WO PCT/NL2005/000752 patent/WO2006043809A1/en active Application Filing
- 2005-10-20 JP JP2007537823A patent/JP2008517903A/en active Pending
- 2005-10-20 ES ES05795367T patent/ES2318548T3/en active Active
- 2005-10-20 DK DK05795375T patent/DK1805306T3/en active
- 2005-10-20 PT PT05795379T patent/PT1805307E/en unknown
-
2007
- 2007-03-27 NO NO20071600A patent/NO20071600L/en not_active Application Discontinuation
- 2007-03-27 NO NO20071599A patent/NO20071599L/en not_active Application Discontinuation
- 2007-03-27 NO NO20071601A patent/NO20071601L/en not_active Application Discontinuation
- 2007-04-19 US US11/737,679 patent/US20070225230A1/en not_active Abandoned
- 2007-04-19 US US11/737,588 patent/US20070224589A1/en not_active Abandoned
- 2007-04-20 US US11/738,393 patent/US20070224680A1/en not_active Abandoned
- 2007-07-16 US US11/778,210 patent/US20080085273A1/en not_active Abandoned
Non-Patent Citations (1)
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